Keratinocyte growth factor (KGF) is a growth factor specific for epithelial cells that was first identified in conditioned medium of a human embryonic lung fibroblast cell line. Rubin et al., Proc. Natl. Acad. Sci. USA 86:802-806 (1989). Expression of messenger RNA for KGF has been detected in several stromal fibroblast cell lines derived from epithelial tissues at various stages of development. The transcript for KGF was also evident in RNA extracted from normal adult kidney and organs of the gastrointestinal tract. Finch et al., Science 245:752-755 (1989). Evidence that KGF is secreted from fibroblasts in culture and is expressed in vivo in the dermis but not epidermis indicates that KGF may be an important normal paracrine effector of keratinocyte proliferation. Studies have shown that KGF is as potent as EGF in stimulating the proliferation of primary or secondary human keratinocytes in tissue culture. Marchese et al., J. Cell. Phys. 144:326-332 (1990).
Ex vivo and in vivo studies in normal adult animals have shown that KGF produces changes in hair follicle morphogenesis, hepatocyte proliferation, and epithelial cell proliferation in the lung, breast, pancreas, stomach, small intestine, and large intestine. Panos et al., J. Clin. Invest. 92:969-977 (1993); Ulich et al., Am. J. Path. 144:862-868 (1994); Yi et al., Am. J. Path. 145:80-85 (1994); and Ulich et al., J. Clin. Invest. 93:1298-1306 (1994). The role of KGF in embryonic or neonatal development has not been studied in detail; however, KGF has been documented to be an important mediator of seminal vesicle development in the newborn mouse. Alarid et al., P.N.A.S. 91:1074-1078 (1994).
Published PCT patent application WO 90/08771 describes the purification of KGF from the conditioned medium of a human embryonic fibroblast cell line, the partial amino acid sequencing of purified KGF, the cloning of the gene, and the expression of the gene in bacterial cells to yield biologically active recombinant KGF. The aforementioned publication discloses that KGF or KGF-like polypeptides can be used as wound healing agents for burn wounds or to stimulate transplanted corneal tissue. In fact, KGF has been demonstrated to increase re-epithelialization and increased thickness of the epithelium when recombinant KGF was topically applied to wounds surgically induced in the rabbit ear or in porcine skin. Pierce et al., J. Exp. Med. 179:831-840 (1994); and Staiano-Coico et al., J. Exp. Med. 178:865-878 (1993).